Résumé :
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Communication n° 8 Beta-adrenergic receptor-mediated, cAMP, and protein kinase A-dependent (PKA) stimulation of select cardiac ionic currents, such as the rapid outward potassium current (IKr), controls ventricular action potential duration at higher heart rates. HERG (KCNH2) gene mutations associated with congenital long QT syndrome (LQT2) affect IKr activity. Frequently, sympathetic nervous system (SNS) activation due to physical activity or emotional stress triggers lethal arrhythmias in LQT2 patients. Beta-adrenergic stimulation of HERG channel activity is amplified and prolonged in vitro by 14-3-3e.We now provide genetic and functional evidence that HERG channel regulation by 14-3-3e is of physiological significance in humans. We have characterized novel LQT2 mutations affecting the C-terminus of HERG subunits and eliminating a C-terminal PKA phosphorylation site. When expressed in CHO cells, they produced functional HERG channels with wild-type properties. Upon co-expression with 14-3-3e however the mutant channels bound 14-3-3e but did not respond with an increase in IKr amplitude as normally seen. This effect was dominant when wild-type and mutant subunits were co-expressed along with 14-3-3e. We conclude that the attenuated functional effect of 14-3-3e on HERG channels harboring the novel LQT2 mutations demonstratess the physiological importance of coupling beta-adrenergic stimulation and HERG channel activity, which is key to SNS control of cardiac electric activity.
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